Various central nervous system disorders such as anxiety, depression, motor disorders, etc., are believed to involve a disturbance of the neurotransmitter 5-hydroxytryptamine (5-HT) or serotonin. Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, motor activity, feeding behavior, sexual activity, and neuroendocrine regulation among others. The effects of serotonin are regulated by the various 5-HT receptor subtypes. Known 5-HT receptors include the 5-HT1 family (e.g. 5-HT1A), the 5-HT2 family (e.g. 5-HT2A), 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 subtypes.
The recently identified human 5-hydroxytryptamine-6 (5-HT6) receptor subtype has been cloned, and the extensive distribution of its mRNA has been reported. Highest levels of 5-HT6 receptor mRNA have been observed in the olfactory tubercle, the striatum, nucleus accumbens, dentate gyrus and CA1, CA2 and CA3 regions of the hippocampus. Lower levels of 5-HT6 receptor mRNA were seen in the granular layer of the cerebellum, several diencephalic nuclei, amygdala and in the cortex. Northern blots have revealed that 5-HT6 receptor mRNA appears to be exclusively present in the brain, with little evidence for its presence in peripheral tissues. The high affinity of a number of antipsychotic agents for the 5-HT6 receptor, in addition to its mRNA localization in striatum, olfactory tubercle and nucleus accumbens suggests that some of the clinical actions of these compounds may be mediated through this receptor. Therefore, 5-HT6 receptor ligands are believed to be of potential use in the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorder, attention defecit disorders, migraine, cognitive memory enhancement (e.g. for the treatment of Alzheimer""s disease), sleep disorders, feeding disorders (e.g. anorexia or bulimia), neurodegenerative disorders (e.g. head trauma or stroke),panic attacks, withdrawal from drug abuse (e.g. cocaine, ethanol, nicotine or benzodiazepines), schizophrenia, or the like; or in the treatment of certain gastrointestinal disorders such as irritable bowel syndrome.
Therefore, it is an object of this invention to provide compounds which are useful as therapeutic agents in the treatment of a variety of central nervous system disorders related to or affected by the 5-HT6 receptor.
It is another object of this invention to provide therapeutic methods and pharmaceutical compositions useful for the treatment of central nervous system disorders related to or affected by the 5-HT6 receptor.
It is a feature of this invention that the compounds provided may also be used to further study and elucidate the 5-HT6 receptor.
These and other objects and features of the invention will become more apparent by the detailed description set forth hereinbelow.
The present invention provides a compound of formula 
wherein
W is SO2, CO, CONH, CSNH or CH2;
X is CR7 or N;
Y is CR8 or N with the proviso that when X is N, then Y must be CR8;
Z is O, SOp, or NR9;
R1 and R2 are each independently H or C1-C6alkyl;
n is an integer of 2, 3 or 4;
R3 and R4 are each independently H, CNR10NR11R12 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted, or R3 and R4 may be taken together with the atom to which they are attached to form an optionally substituted 3- to 6-membered ring optionally containing an additional heteroatom selected from O, N or S;
R5 is H, halogen, CN, OR13, CO2R14, CONR15R16, CNR17NR18R19, SO2NR20R21, SOqR22 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted;
m is an integer of 1, 2 or 3;
p and q are each independently 0 or an integer of 1 or 2;
R6 is an optionally substituted C1-C6alkyl, aryl or heteroaryl group;
R7 and R8 are each independently H, halogen or a C1-C6 alkyl, aryl, heteroaryl or C1-C6alkoxy group each optionally substituted;
R9 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R10, R11, R12, R15, R16, R17, R18 and R19 are each independently H or C1-C4alkyl;
R13 is H, COR23 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, aryl or heteroaryl group each optionally substituted;
R14 is H or a C1-C6alkyl, aryl or heteroaryl group each optionally substituted;
R20 and R21 are each independently H or a C1-C6alkyl, aryl or heteroaryl group each optionally substituted; and
R22 and R23 are each independently an optionally substituted C1-C6alkyl, aryl or heteroaryl group; or
a pharmaceutically acceptable salt thereof.
The present invention also provides methods and compositions useful for the therapeutic treatment of central nervous system disorders related to or affected by the 5-HT6 receptor.
The 5-hydroxytryptamine-6 (5-HT6) receptor is one of the most recent receptors to be identified by molecular cloning. Its ability to bind a wide range of therapeutic compounds used in psychiatry, coupled with its intriguing distribution in the brain has stimulated significant interest in new compounds which are capable of interacting with or affecting said receptor. At present, there are no known fully selective agonists. Significant efforts are being made to understand the possible role of the 5-HT6 receptor in psychiatry, cognitive dysfunction, motor function and control, memory, mood and the like. To that end, compounds which demonstrate a binding affinity for the 5-HT6 receptor are earnestly sought both as an aid in the study of the 5-HT6 receptor and as potential therapeutic agents in the treatment of central nervous system disorders.
Surprisingly, it has now been found that 1-aryl- or 1-alkylsulfonylbenzazole derivatives of formula I demonstrate 5-HT6 affinity. Advantageously, said benzazole derivatives may be used as effective therapeutic agents for the treatment of central nervous system (CNS) disorders associated with or affected by the 5-HT6 receptor. Accordingly, the present invention provides 1-alkyl- or 1-arylsulfonylbenzazole derivatives of formula I 
wherein
W is SO2, CO, CONH, CSNH or CH2;
X is CR, or N;
Y is CR8 or N with the proviso that when X is N, then Y must be CR,;
Z is O, SOp or NR9;
R1 and R2 are each independently H or C1-C6alkyl; n is an integer of 2, 3 or 4;
R3 and R4 are each independently H, CNR10NR11R12, or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted, or R3 and R4 may be taken together with the atom to which they are attached to form an optionally substituted 3- to 6-membered ring optionally containing an additional heteroatom selected from O, N or S;
R5 is H, halogen, CN, OR13, CO2R14, CONR15R16, CNR17NR18R19, SO2NR20R21, SOqR22 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted;
m is an integer of 1, 2 or 3;
p and q are each independently 0 or an integer of 1 or 2;
R6 is an optionally substituted C1-C6alkyl, aryl or heteroaryl group;
R7 and R8 are each independently H, halogen or a C1-C6alkyl, aryl, heteroaryl or C1-C6alkoxy group each optionally substituted;
R9 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R10, R11, R12, R15, R17, R18, and R19 are each independently H or C1-C4alkyl;
R13 is H, COR23 or a C1-C6alkyl, C2-C6alkenyl, C1-C6alkynyl, aryl or heteroaryl group each optionally substituted;
R14 is H or a C1-C6alkyl, aryl or heteroaryl group each optionally substituted;
R20and R21 are each independently H or a C1-C6alkyl, aryl or heteroaryl group each optionally substituted; and
R22 and R23 are each independently an optionally substituted C1-C6alkyl, aryl or heteroaryl group; or
a pharmaceutically acceptable salt thereof.
As used in the specification and claims, the term halogen designates Br, Cl, I or F and the term cycloheteroalkyl designates a C5-C7cycloalkyl ring system containing 1 or 2 heteroatoms, which may be the same or different, selected from N, O or S and optionally containing one double bond. Exemplary of the cycloheteroalkyl ring systems included in the term as designated herein are the following rings wherein Q is NR, O or S; and R is H or an optional substituent as defined hereinbelow. 
Similarly, as used in the specification and claims, the term heteroaryl designates a C1-C10 aromatic ring system containing 1 or 2 heteroatoms, which may be the same or different, selected from N, O or S. Such heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl, indolinyl, benzothienyl, benzofuranyl, benzisoxazolyl and the like; the term haloalkyl designates a CnH2n+1 group having from one to 2n+1 halogen atoms which may be the same or different; and the term haloalkoxy designates an OCnH2n+1 group having from one to 2n+1 halogen atoms which may be the same or different.
In the specification and claims, when the terms C1-C6alkyl, C2-C6alkenyl, C2-C6alkynl, C1-C7cycloalkyl, cycloheteroalkyl, aryl or heteroaryl are designated as being optionally substituted, the substituent groups which are optionally present may be one or more of those customarily employed in the development of pharmaceutical compounds or the modification of such compounds to influence their structure/activity, persistence, absorption, stability or other beneficial property. Specific examples of such substituents include halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl or cycloalkyl groups, preferably halogen atoms or lower alkyl groups. Typically, 0-3 substituents may be present. When any of the foregoing substituents represents or contains an alkyl substituent group, this may be linear or branched and may contain up to 12, preferably up to 6, more preferably up to 4 carbon atoms.
Pharmaceutically acceptable salts may be any acid addition salt formed by a compound of formula I and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid or the like.
Preferred compounds of the invention are those compounds of formula I wherein W is SO2 or CO. Also preferred are those compounds of formula I wherein Z is O. Another group of preferred compounds of the invention are those compounds of formula I wherein n is 2. Further preferred compounds of the invention are those compounds of formula I wherein R6 is an aryl or heteroaryl group each optionally substituted.
More preferred compounds of the invention are those compounds of formula I wherein W is SO2; R1 and R2 are H; and n is 2. Another group of more preferred compounds of the invention are those compounds of formula I wherein W is SO2; Z is O; X is CR7; and R3 and R4 are taken together with the atom to which they are attached to form a 5- or 6-membered ring optionally containing one oxygen atom.
Among the preferred compounds of the invention are:
2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethylamine;
4-(2-morpholin-4-ylethoxy)-1-(phenylsulfonyl)-1H-indole;
1-(phenylsulfonyl)-4-(2-piperidin-1-ylethoxy)-1H-indole;
N-(2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethyl)-tetrahydro-2H-pyran-4-amine;
N,N-bis(3-methoxybenzyl)-2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethanamine;
N-(3-methoxybenzyl)-2-{[1-(phenylsulfonyl)-1H-indol-4-yl] oxy}ethanamine;
N,N-dimethyl-2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethanamine;
1-(phenylsulfonyl)-4-[2-(1-piperidinyl)ethoxy]-1H-indazole;
2-{[1-(phenylsulfonyl)-1H-indazol-4-yl]oxy}ethylamine;
N-(2-{[1-(phenylsulfonyl)-1H-indazol-4-yl]oxy}ethyl)tetrahydro-2H-pyran-4-amine;
N-(2-{[1-(phenylsulfonyl)-1H-indazol-4-yl]oxy}ethyl)tetrahydro-2H-thiopyran-4-amine;
1-[(4-nitrophenyl)sulfonyl]-4-[2-(1-piperidinyl)ethoxy]-1H-indazole;
1-[(4-fluorophenyl)sulfonyl]-4-[2-(1-piperidinyl)ethoxy]-1H-indazole;
4-({4-(2-(1-piperidinyl)ethoxy]-1H-indazol-1-yl}sulfonyl)aniline; or
a pharmaceutically acceptable salt thereof.
Compounds of the invention may be prepared using conventional synthetic methods and, if required, standard separation and isolation techniques. For example, compounds of formula I wherein W is SO2, R1 and R2 are H, and Z is O may be prepared by reacting an hydroxybenzazole intermediate of formula II with a haloalkanol of formula III in the presence of triphenylphosphine and diethyl azodicarboxylate to give the haloalkoxy derivative of formula IV; sulfonating the formula IV derivative to give the 1-sulfonylbenzazole compound of formula V; and displacing the halo group of said formula V compound with the appropriate amine to give the desired compounds of formula Ia. The reaction sequence is illustrated in flow diagram I wherein Hal designates a halogen atom. 
Alternatively, compounds of formula Ia may be prepared by reacting the intermediate of formula V with NaN3 to form the corresponding benzazolyloxyalkylazide of formula VI; reducing said formula VI azide with triphenylphosphine to give the formula I compound wherein Z is O and R1, R2, R3 and R4 are H(Ib); and optionally alkylating said formula Ib compound to give compounds of formula Ia. The reactions are illustrated in flow diagram II. 
Similarly, compounds of formula I wherein W is SO2 and Z is S may be prepared by utilizing the appropriate benzazolylthiol starting material and employing essentially the same reaction sequences shown hereinabove in flow diagrams I and II.
Compounds of formula I wherein W is SO2 and Z is NH (Ic) may be prepared by sulfonating a nitrobenzazole intermediate of formula VII to give the corresponding 1-sulfonyl derivative of formula VIII; reducing the formula VIII compound to give the corresponding amine of formula IX; reacting said amine with a haloalkylaldehyde of formula X to give the haloalkylamine derivative of formula XI; and displacing the halo group of said formula XI derivative with the appropriate amine to give the desired compounds of formula Ic. The reaction sequence is shown in flow diagram III. 
Compounds of formula I wherein W is Co and Z is O, may be prepared by reacting a compound of formula IV with the appropriate isocyanate or carbonyl or carbamoyl halide in the presence of a base. Using these and other conventional methods, compounds of formula I may be prepared from readily available starting materials.
Advantageously, the inventive compound of formula I may be utilized in the treatment of central nervous system disorders relating to or affected by the 5-HT6 receptor such as motor, mood, psychiatric, cognitive, neurodegenerative, or the like disorders. Accordingly, the present invention provides a method for the treatment of a disorder of the central nervous system (CNS) related to or affected by the 5-HT6 receptor in a patient in need thereof which comprises providing said patient a therapeutically effective amount of a compound of formula I as described hereinabove. The compounds may be provided by oral or parenteral administration or in any common manner known to be an effective administration of a therapeutic agent to a patient in need thereof.
The therapeutically effective amount provided in the treatment of a specific CNS disorder may vary according to the specific condition(s) being treated, the size, age and response pattern of the patient, the severity of the disorder, the judgment of the attending physician and the like. In general, effective amounts for daily oral administration may be about 0.91 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg and effective amounts for parenteral administration may be about 0.1 to 100 mg/kg, preferably about 0.5 to 50 mg/kg.
In actual practice, the compounds of the invention are provided by administering the compound or a precursor thereof in a solid or liquid form, either neat or in combination with one or more conventional pharmaceutical carriers or excipients. Accordingly, the present invention provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I as described hereinabove.
Solid carriers suitable for use in the composition of the invention include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aides, binders, tablet-disintegrating agents or encapsulating materials. In powders, the carrier may be a finely divided solid which is in admixture with a finely divided compound of formula I. In tablets, the formula I compound may be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Said powders and tablets may contain up to 99% by weight of the formula I compound. Solid carriers suitable for use in the composition of the invention include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Any pharmaceutically acceptable liquid carrier suitable for preparing solutions, suspensions, emulsions, syrups and elixirs may be employed in the composition of the invention. Compounds of formula I may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a pharmaceutically acceptable oil or fat, or a mixture thereof. Said liquid composition may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers, osmo-regulators, or the like. Examples of liquid carriers suitable for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) or their derivatives, or oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier may also be an oily ester such as ethyl oleate or isopropyl myristate.
Compositions of the invention which are sterile solutions or suspensions are suitable for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. Inventive compositions suitable for oral administration may be in either liquid or solid composition form.
For a more clear understanding, and in order to illustrate the invention more clearly, specific examples thereof are set forth hereinbelow. The following examples are merely illustrative and are not to be understood as limiting the scope and underlying principles of the invention in any way.
Unless otherwise stated, all parts are parts by weight. The terms HPLC and NMR designate high performance liquid chromatography and nuclear magnetic resonance, respectively. The terms EtOAc and Et2O designate ethyl acetate and diethyl ether, respectively.